Transcript: Elizabeth Volkmann, MD, on Systemic Sclerosis and the Gut Microbiome

Rebecca Mashaw:  Hello everyone, and welcome to another installment of "Podcasts360," your go-to resource for medical news and clinical updates. I'm your moderator, Rebecca Mashaw, with Rheumatology Consultant. Today, we will talk to Dr. Elizabeth Volkmann, the founder and director of the Connective Tissue Disease-Interstitial Lung Disease integrative clinic at the University of California, Los Angeles. She's going to give us an overview of her recent research into the relationship between the gut microbiome and systemic sclerosis. Thank you so much for being here today, Dr. Volkmann. In your review published last year in the "European Journal of Rheumatology," you state that the therapeutic options for treating systemic sclerosis have increased in recent years, but they primarily target symptoms and don't really modify the course of the disease. You've conducted research into the gut microbiome and systemic sclerosis in an effort to discover new treatment targets. What differences have you found in the gut microbiota and systemic sclerosis patients compared with those of healthy controls? Dr. Elizabeth Volkmann: That's a great question. In the review, we were really highlighting looking for treatment options for the GI disease of scleroderma. Some of the other manifestations of scleroderma, like the lung disease and the skin disease, we do have some options for. The GI disease is really something where, as you said, the treatments just target symptoms and don't really get at a cure or modifying the disease course. This is what initially sparked my interest, to look at the gut microbiome as potentially being important mediator of the pathogenesis for the disease. In the first study that was ever done to investigate the microbiome in scleroderma patients at UCLA, we compared scleroderma patients with healthy controls. What we found was that patients with scleroderma had higher levels of what we call pathobiont bacteria. These are bacteria that have been found in prior studies to be associated with more inflammation and more symptoms than other disease states. Then, we found lower levels of what we call commensal bacteria. These are bacteria that we think may actually be protective against inflammation and contribute to more of a healthy gut microbiome. In the study, we also found that the extent of the dysbiosis or the imbalance was associated with symptoms. Patients who had more GI symptoms actually had greater imbalances in their gut bacteria. Rebecca:  Your research has also looked at how external environmental influences could contribute to these alterations in the gastrointestinal microbiota. What have you found to date this respect? Is this an area that warrants more, and more in-depth, research? Dr. Volkmann:  Another great question. Absolutely, this is definitely an evolving area of research. I think it's important for it to consider external environmental factors when you're doing this kind of research. For example, we did a follow-up study where we looked at scleroderma patients, not only at UCLA but scleroderma patients from Norway. We found significant differences between the two groups and probably most of those can be explained external environmental influences. One of the areas I'm particularly interested in is nutrition and diet, because this is one way to modify the gut microbiome which doesn't have a lot of side effects like taking a drug, but really can have substantial effect on the balance of gut bacteria. We recently did a study, which we hope to present at our upcoming American College of Rheumatology meeting this fall, where we looked at a particular diet called the Low-FODMAP diet, and we looked to see whether this had any impact on the gut microbiome. I think a lot more research is needed in this area, but that first study we did comparing two different [groups of] scleroderma patients really showed us there are probably other factors that we need to consider when we do this research. Rebecca:  You also noted that most studies of the gut microbiome focused on studying bacteria, in part because the analysis of viruses and fungi are more challenging. You and your colleagues have taken the course of examining the role of gut microbiota in systemic sclerosis patients by analyzing 16S rRNA in metogenomic sequencing. What have you learned? What else needs to be clarified in further research? Dr. Volkmann: This is a complicated issue, but there are different ways to characterize the gut microbiome. Obviously, most people look at bacteria, and this is what you use the 16S sequencing for. Then there's other inhabitants of the gut microbiome that could be contributing to these disease states. That could include viruses and fungi. What we're trying to do now is expand our research efforts doing something called "shotgun metogenomics," which you reference. In this we'll also be able to look at viruses and fungi. In addition, we're also taking the steps to look at what's called "metabolomics." This is looking at metabolites that are produced by the gut bacteria. It may not be that just the bacteria alone are what's causing inflammation. It could be the byproducts of the bacteria that interface with the immune system that could cause inflammation. The next step in this in what we're doing right now, and we hope to have results for in the coming year, is to look not only at the bacteria, the viruses, and the fungi but also to look at the metabolic products. Rebecca:  Some research has shown that up to half of the all patients with systemic sclerosis who also have esophageal disease and about 20% of those who have small bowel involvement remain asymptomatic until severe damage to the tissues has already taken place. Are there any clinical signs or tests that could help identify these conditions before they manifest as more serious and complex disease? Dr. Volkmann:  This is a very important clinical issue because oftentimes, patients are diagnosed with their GI complications at a later disease stage. This could be for a variety of reasons. One is that sometimes patients aren't always comfortable disclosing problems they have with their gut. Sometimes these are very personal things like diarrhea, fecal incontinence, and they may not be things that someone would voluntarily talk about unless the physician asks the patient. I say, first and foremost, it's really important to have an open dialogue with patients about these symptoms. Otherwise, the patients may not even relay that they're having these symptoms. Another important point is that some of the symptoms that they do have, —for example, cough— someone will say, "Well, their cough is due to their lung disease." But in fact, what we've found in studies is that in patients with chronic cough, about half the time it's due to the lung disease. The other half is due to esophageal disease, because cough is a very common symptom of reflux disease. Again, it's really important to not only ask the patients about their symptoms but always tease out what is the cause of the symptoms. The second part of your question that is really important and timely is how can we test these patients maybe even when they aren't having these symptoms, even when we ask them about symptoms, we could do tests? This is another evolving area of research because at present, we don't have great imaging like we do with the lungs or other parts of the disease where we can screen for these manifestations. Again, I think that this is an ongoing area of research. I have a really productive collaborator right now at Johns Hopkins, and she has been looking at motility studies in patients to be able to characterize how the gut moves in different parts. This could be potentially something that we do in the future in all patients. Rebecca:  Systemic sclerosis is an extremely complex disease. In one of your papers, you write about how combining therapies to address the individual manifestations of systemic sclerosis is a cornerstone to the comprehensive management of this condition. What kinds of combination therapies are you using now on your patients and what newer therapies are showing promise in treatment of systemic sclerosis? Dr. Volkmann:  Combining therapies is something that we've done in a lot of different diseases throughout the field of rheumatology. For example, in rheumatoid arthritis and in lupus, we often combine therapies. In systemic sclerosis, I would say that because we didn't have a lot of therapies available, there weren't even therapies to combine. Fortunately, the pipeline of this disease state is really expanding quite rapidly. We do now have an opportunity to test the combination of therapies. One example of this is the treatment of interstitial lung disease or pulmonary fibrosis. Traditionally, we used immunosuppressant therapies such as mycophenolate mofetil or cyclophosphamide to treat this dimension of scleroderma. Now, recently approved is the antifibrotic agent, nintedanib. This is a medication that works in a little bit of a different way than immunosuppressants. Studies are being done now to look at the combinations — combining an antifibrotic like nintedanib and pirfenidone with an immunosuppressant — to see that you can get an even greater treatment response. I think this is the future of this, to figure out how to combine these therapies and how to personalize it to the patient. Some patients may do just fine with one therapy, but in other patients, they may need two therapies to achieve adequate treatment response. I do believe that this is really the future of clinical research in this disease. Rebecca:  You've written that you believe this research into the gut microbiome may perhaps shed light on the pathogenesis of systemic sclerosis and may lead to the discovery of biomarkers that can predict the development of specific features of this disease, including interstitial lung disease, which is one of your specialty areas in treatment and research. What do you think needs to happen next in research to make progress in these areas? Dr. Volkmann:  This is a really interesting topic. I would say that in terms of interstitial lung disease, we know that this is the leading cause of death in these patients, but it is often diagnosed at a later disease stage because patients weren't screened adequately or they may not have symptoms early on. One of the things that we're very interested in is using the gut microbiome as a screening tool to be able to detect interstitial lung disease. This could then prompt a physician to then order a high-resolution chest CT to make the firm diagnosis. What we found when we compared the UCLA cohort of scleroderma patients to the Norwegian cohort of scleroderma patients was that, in addition to patients residing in completely different countries, we found that a significantly greater proportion of patients at the UCLA site had interstitial lung disease and a much lower proportion had interstitial lung disease at the Norway site. This made us think, "Hey, maybe there're really differences that relate to lung disease." Now what we've endeavored to do is look within our own cohort. We've increased the size of this cohort. Indeed, we found that the presence of interstitial lung disease is associated with alterations in the gut microbiome. I have a large grid now that we're just starting to look at this issue in two independent cohorts, both at UCLA and in Sweden to be able to figure out, "Can we use the gut microbiome to screen for the presence of interstitial lung disease, and can we use it to also predict the severity of interstitial lung disease?" Rebecca:  Again, thank you for joining us today to talk about this very interesting topic, and we certainly look forward to hearing more about your research in the future.